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https://www.readbyqxmd.com/read/29352227/ly2087101-and-dfbr-share-transmembrane-binding-sites-in-the-%C3%AE-4-3-%C3%AE-2-2-nicotinic-acetylcholine-receptor
#1
Farah Deba, Hamed I Ali, Abisola Tairu, Kara Ramos, Jihad Ali, Ayman K Hamouda
Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have potential therapeutic application in neuropathologies associated with decrease in function or loss of nAChRs. In this study, we characterize the pharmacological interactions of the nAChRs PAM, LY2087101, with the α4β2 nAChR using mutational and computational analyses. LY2087101 potentiated ACh-induced currents of low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs with similar potencies albeit to a different maximum potentiation (potentiation I max  = ~840 and 450%, respectively)...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29352080/functional-analysis-of-cancer-associated-dna-polymerase-%C3%AE%C2%B5-variants-in-saccharomyces-cerevisiae
#2
Stephanie R Barbari, Daniel P Kane, Elizabeth A Moore, Polina V Shcherbakova
DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase ε (Polε). They have been hypothesized to result from defective proofreading. However, modeling in yeast of the most common variant, Polε-P286R, produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors...
January 19, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29351633/evolutionary-genetics-of-cytoplasmic-incompatibility-genes-cifa-and-cifb-in-prophage-wo-of-wolbachia
#3
Amelia R I Lindsey, Danny W Rice, Sarah R Bordenstein, Andrew W Brooks, Seth R Bordenstein, Irene L G Newton
The bacterial endosymbiont Wolbachia manipulates arthropod reproduction to facilitate its maternal spread through host populations. The most common manipulation is cytoplasmic incompatibility (CI): Wolbachia-infected males produce modified sperm that cause embryonic mortality, unless rescued by embryos harboring the same Wolbachia. The genes underlying CI, cifA and cifB, were recently identified in the eukaryotic association module of Wolbachia's prophage WO. Here, we use transcriptomic and genomic approaches to address three important evolutionary facets of the cif genes...
January 17, 2018: Genome Biology and Evolution
https://www.readbyqxmd.com/read/29351434/cub-domain-containing-protein-1-cdcp1-negatively-regulates-tgf%C3%AE-signaling-and-myofibroblast-differentiation
#4
Nina Noskovičová, Katharina Heinzelmann, Gerald Burgstaller, Jürgen Behr, Oliver Eickelberg
Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix (ECM) proteins in the connective tissue. The profibrotic cytokine, transforming growth factor-beta 1 (TGFβ1) activates and transdifferentiates fibroblasts into αSMA-expressing myofibroblasts, which exhibit increased ECM secretion, in particular collagens. Little information, however, exists about cell-surface molecules on fibroblasts that mediate this transdifferentiation process. We recently identified, using unbiased cell-surface proteome analysis, Cub domain containing protein 1 (CDCP1) to be strongly downregulated by TGFβ1...
January 4, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29349599/evolution-of-eukaryal-and-archaeal-pseudouridine-synthase-pus10
#5
Elisabeth Fitzek, Archi Joardar, Ramesh Gupta, Matt Geisler
In archaea, pseudouridine (Ψ) synthase Pus10 modifies uridine (U) to Ψ at positions 54 and 55 of tRNA. In contrast, Pus10 is not found in bacteria, where modifications at those two positions are carried out by TrmA (U54 to m5U54) and TruB (U55 to Ψ55). Many eukaryotes have an apparent redundancy; their genomes contain orthologs of archaeal Pus10 and bacterial TrmA and TruB. Although eukaryal Pus10 genes share a conserved catalytic domain with archaeal Pus10 genes, their biological roles are not clear for the two reasons...
January 18, 2018: Journal of Molecular Evolution
https://www.readbyqxmd.com/read/29348368/defining-the-physiological-role-of-srp-in-protein-targeting-efficiency-and-specificity
#6
Elizabeth A Costa, Kelly Subramanian, Jodi Nunnari, Jonathan S Weissman
The signal recognition particle (SRP) enables cotranslational delivery of proteins for translocation into the endoplasmic reticulum (ER), but its full in vivo role remains incompletely explored. We combined rapid auxin-induced SRP degradation with proximity-specific ribosome profiling to define SRP's in vivo function in yeast. Despite the classic view that SRP recognizes N-terminal signal sequences, we show that SRP was generally essential for targeting transmembrane domains regardless of their position relative to the N terminus...
January 18, 2018: Science
https://www.readbyqxmd.com/read/29346777/prrt2-regulates-synaptic-fusion-by-directly-modulating-snare-complex-assembly
#7
Jeff Coleman, Ouardane Jouannot, Sathish K Ramakrishnan, Maria N Zanetti, Jing Wang, Vincenzo Salpietro, Henry Houlden, James E Rothman, Shyam S Krishnakumar
Mutations in proline-rich transmembrane protein 2 (PRRT2) are associated with a range of paroxysmal neurological disorders. PRRT2 predominantly localizes to the pre-synaptic terminals and is believed to regulate neurotransmitter release. However, the mechanism of action is unclear. Here, we use reconstituted single vesicle and bulk fusion assays, combined with live cell imaging of single exocytotic events in PC12 cells and biophysical analysis, to delineate the physiological role of PRRT2. We report that PRRT2 selectively blocks the trans SNARE complex assembly and thus negatively regulates synaptic vesicle priming...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29344581/glycophorin-c-sialylation-regulates-lu-bcam-adhesive-capacity-during-erythrocyte-aging
#8
T R L Klei, D Z de Back, P J Asif, P J J H Verkuijlen, M Veldthuis, P C Ligthart, J Berghuis, E Clifford, B M Beuger, T K van den Berg, R van Zwieten, W El Nemer, R van Bruggen
Lutheran/basal cell adhesion molecule (Lu/BCAM) is a transmembrane adhesion molecule expressed by erythrocytes and endothelial cells that can interact with the extracellular matrix protein laminin-α5. In sickle cell disease, Lu/BCAM is thought to contribute to adhesion of sickle erythrocytes to the vascular wall, especially during vaso-occlusive crises. On healthy erythrocytes however, its function is unclear. Here we report that Lu/BCAM is activated during erythrocyte aging. We show that Lu/BCAM-mediated binding to laminin-α5 is restricted by interacting, in cis, with glycophorin-C-derived sialic acid residues...
January 9, 2018: Blood Advances
https://www.readbyqxmd.com/read/29343851/ndrg2-facilitates-colorectal-cancer-differentiation-through-the-regulation-of-skp2-p21-p27-axis
#9
Liangliang Shen, Xuan Qu, Huichen Li, Chunsheng Xu, Mengying Wei, Qinhao Wang, Yi Ru, Bei Liu, Yuqiao Xu, Kai Li, Junbi Hu, Lifeng Wang, Yongzheng Ma, Mengyang Li, Xiaofeng Lai, Lei Gao, Kaichun Wu, Libo Yao, Jianyong Zheng, Jian Zhang
Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage...
January 18, 2018: Oncogene
https://www.readbyqxmd.com/read/29343613/restricted-hiv-1-env-glycan-engagement-by-lectin-reengineered-davei-protein-chimera-is-sufficient-for-lytic-inactivation-of-the-virus
#10
Bibek Parajuli, Kriti Acharya, Harry C Bach, Bijay Parajuli, Shiyu Zhang, Amos B Smith, Cameron F Abrams, Irwin Chaiken
We previously reported first generation recombinant DAVEI construct, a dual action virus entry inhibitor composed of cyanovirin-N (CVN) fused to a membrane proximal external region (MPER) or its derivative peptide Trp3. DAVEI exhibits potent and irreversible inactivation of HIV-1 viruses by dual engagement of gp120 and gp41. However, the promiscuity of CVN to associate with multiple glycosylation sites in gp120 and its multivalency limit current understanding of the molecular arrangement of the DAVEI molecules on trimeric spike...
January 17, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29343551/two-subunits-of-the-exocyst-sec3p-and-exo70p-can-function-exclusively-on-the-plasma-membrane
#11
Dongmei Liu, Xia Li, David Shen, Peter Novick
The exocyst is an octameric complex that tethers secretory vesicles to the plasma membrane in preparation for fusion. We anchored each subunit with a transmembrane (TM) domain at its N- or C-terminus. Only N-terminally anchored TM-Sec3p and C-terminally anchored Exo70p-TM proved functional. These findings orient the complex with respect to the membrane and establish that Sec3p and Exo70p can function exclusively on the membrane. The functions of TM-Sec3p and Exo70p-TM were largely unaffected by blocks in endocytic recycling suggesting that they act on the plasma membrane, rather than on secretory vesicles...
January 17, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29342275/hot-spot-kif5a-mutations-cause-familial-als
#12
David Brenner, Rüstem Yilmaz, Kathrin Müller, Torsten Grehl, Susanne Petri, Thomas Meyer, Julian Grosskreutz, Patrick Weydt, Wolfgang Ruf, Christoph Neuwirth, Markus Weber, Susana Pinto, Kristl G Claeys, Berthold Schrank, Berit Jordan, Antje Knehr, Kornelia Günther, Annemarie Hübers, Daniel Zeller, Christian Kubisch, Sibylle Jablonka, Michael Sendtner, Thomas Klopstock, Mamede de Carvalho, Anne Sperfeld, Guntram Borck, Alexander E Volk, Johannes Dorst, Joachim Weis, Markus Otto, Joachim Schuster, Kelly Del Tredici, Heiko Braak, Karin M Danzer, Axel Freischmidt, Thomas Meitinger, Tim M Strom, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt
Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis...
January 12, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29342135/structures-of-%C3%AE-klotho-reveal-a-zip-code-like-mechanism-for-endocrine-fgf-signalling
#13
Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, Leiliane P Sousa, Francisco Tome, Els Pardon, Jan Steyaert, Mark A Lemmon, Irit Lax, Joseph Schlessinger
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342012/diffuse-chorioretinopathy-without-serous-detachment-associated-with-cardiac-transplantation
#14
Michael F Marmor
PURPOSE: To analyze an unusual case of widespread chorioretinopathy after cardiac transplantation for its potential etiology and clinical significance. METHODS: Clinical examinations included widefield and macular color and fundus autofluorescence photography, spectral domain optical coherence tomography, fluorescein angiography and indocyanine green angiography, full-field electroretinography, and Goldmann visual fields. PATIENT: A 44-year-old Hispanic woman was referred to rule out retinitis pigmentosa...
January 16, 2018: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/29341872/a-cqferritin-protein-inhibits-white-spot-syndrome-virus-infection-via-regulating-iron-ions-in-red-claw-crayfish-cherax-quadricarinatus
#15
Xiao-Xiao Chen, Yan-Yao Li, Xue-Jiao Chang, Xiao-Lu Xie, Yu-Ting Liang, Ke-Jian Wang, Wen-Yun Zheng, Hai-Peng Liu
It is well known that iron is an essential element for all living organism. The intracellular iron availability is also important for the host's innate immune response to various pathogens, in which the iron homeostasis can be regulated by ferritin due to its iron storage property. In this study, a full-length cDNA sequence of ferritin (named as CqFerritin) was identified with 1410 bp from red claw crayfish Cherax quadricarinatus, which contained an open reading frame of 513 bp, encoding 170 amino acids with a conserved ferritin domain...
January 13, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29339751/jmjc-domain-proteins-modulate-circadian-behaviors-and-sleep-in-drosophila
#16
Nevine A Shalaby, Jorge H Pinzon, Anjana S Narayanan, Eugene Jennifer Jin, Morgan P Ritz, Rachel J Dove, Heike Wolfenberg, Aylin R Rodan, Michael Buszczak, Adrian Rothenfluh
Jumonji (JmjC) domain proteins are known regulators of gene expression and chromatin organization by way of histone demethylation. Chromatin modification and remodeling provides a means to modulate the activity of large numbers of genes, but the importance of this class of predicted histone-modifying enzymes for different aspects of post-developmental processes remains poorly understood. Here we test the function of all 11 non-lethal members in the regulation of circadian rhythms and sleep. We find loss of every Drosophila JmjC gene affects different aspects of circadian behavior and sleep in a specific manner...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29339409/impact-of-homologous-recombination-on-silent-chromatin-in-saccharomyces-cerevisiae
#17
Kathryn J Sieverman, Jasper Rine
Specialized chromatin domains repress transcription of genes within them and present a barrier to many DNA-protein interactions. Silent chromatin in the budding yeast Saccharomyces cerevisiae, akin to heterochromatin of metazoans and plants, inhibits transcription of PolII- and PolIII-transcribed genes, yet somehow grants access to proteins necessary for DNA transactions like replication and homologous recombination. In this study, we adapted a novel assay to detect even transient changes in the dynamics of transcriptional silencing at HML after it served as a template for homologous recombination...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29339296/silent-transmission-of-an-is1294b-deactivated-mcr-1-gene-with-inducible-colistin-resistance
#18
Kai Zhou, Qixia Luo, Qin Wang, Chen Huang, Haifeng Lu, Rossen W A John, Yonghong Xiao, Lanjuan Li
The global dissemination of the mobile colistin resistance mcr-1 is of special concern, as colistin is one of the last-resort antibiotics for the treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria. Here, we characterized an inactive form of mcr-1 in a fluoroquinolone-resistant and colistin-susceptible uropathogenic Escherichia coli isolate (ECO3347). The mcr-1 gene was deactivated by the insertion of a 1.7-Kb IS1294b element flanked by two tetramers (GTTC), and located on a 62-Kb pHNSHP45-like plasmid (p3347-mcr-1)...
January 12, 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29339284/rbmti-6-attenuates-pathophysiological-and-inflammatory-parameters-of-induced-emphysema-in-mice
#19
Adriana Feliciano Alves Duran, Luana de Paiva Neves, Flavia Ribeiro Santos da Silva, Gabriel Capella Machado, Graziele Cristina Ferreira, Juliana D Lourenço, Aparecida Sadae Tanaka, Milton de Arruda Martins, Fernanda D T Q S Lopes, Sergio Daishi Sasaki
Protease/anti-protease imbalance is the main pathogenic mechanism of emphysema and protease inhibitors have been recognized as potential molecules to treat the disease conditions. In this work the rBmTI-6 first domain (rBmTI-6-D1), a recombinant Kunitz-type serine proteinase inhibitor, was used to verify its effect in prevention or minimization of PPE-induced emphysema in mice. C57BL/6 mice were submitted to a PPE-induced emphysema model and treated with rBmTI-6-D1 before the emphysema development. We showed that the rBmTI-6-D1 treatment was sufficient to avoid the loss of elastic recoil, an effective decrease in alveolar enlargement and in the number of macrophages and lymphocytes in bronchoalveolar lavage fluid...
January 12, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29337619/the-role-of-necroptosis-apoptosis-and-inflammation-in-fowl-cholera-associated-liver-injury-in-a-chicken-model
#20
Qiyu Tang, Weitian Li, Na Dai, Yiming Gao, Yu Han, Guofu Cheng, Changqin Gu
Fowl cholera resulting from infection with Pasteurella multocida causes huge economic losses in the poultry industry. Necrotic hepatitis is reported to be a significant lesion associated with fowl cholera in chickens. Clarifying the underlying molecular mechanism of hepatic injury caused by P. multocida infection is needed to develop new strategies to control fowl cholera. Pasteurella multocida Q (the standard reference strain) and P. multocida 1G1 (a clinical strain) were used to infect healthy laying hens...
December 2017: Avian Diseases
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